The long range objectives of this proposal are to elucidate and define the various regulatory (immunologic, anatomic, physiologic and/or endocrinologic) mechanisms which are: 1) operative in normally preventing infertility due to autoimmune responses to either the gonads and/or gametes and 2) involved in eliciting the pathologic state of infertility when such abnormal responses do occur. The specific aims of this proposal are to define the relationships between the pathology, immunology, and genetics of idiopathic male infertility believed to be associated with an autoimmune orchiepididymitis syndrome using the murine model of experimental allergic orchitis (EAO). The fertility status of each strain of the BXH series of recombinant inbred (RI) mice derived from the disease susceptible strain C57BL/6J and the disease resistant strain C3H/H3J will be determined at various times following immunization. We will concomitantly study the underlying testicular lesions, i.e. orchitis, aspermatogenesis, epididymitis, and vasitis, as well as examine the male reproductive tract for the presence of immune deposits and quantitate the accompanying autoimmune responses to sperm and testis specific autoantigens. The fertility status of experimental and control groups of each RI line will be established by test breeding each male with 3 females C57BL/6J animals for 3 weeks following which both the number of pregnancies and the number of concepti per pregnancy will be determined. Testicular lesions will be assessed histologically and the presence and distribution of immune deposits will be determined by IF. The levels of the various isotypes of circulatory anti-sperm and anti-TSDA autoantibodies will be carried out using an ELISA assay on synergeic epididymal sperm and testicular cells. Immunochemical analysis of the various sperm autoantigens will be performed by isotype specific immunoprecipitation of radiolabeled sperm autoantigens and SDS-PAGE. Cell mediated autoimmune responses to testicular cell autoantigens will be determined using the in vitro lymphocyte proliferation assay with estimation of the number of independently segregating gene loci involved in controlling such infertility as well as allow for the determination of genetic linkage, characterization of multiple inheritances, and investigation of the genetic reassortments involving infertility and the associated autoimmune abnormalities.